Relapse to drug use following abstinence is a significant impediment in the long-term treatment of drug abuse and dependence. Conditioned stimuli are believed to be critically involved in activating drug craving and relapse to compulsive drug-taking behavior. Although conditioned cues are now well recognized as a factor in relapse, there remains a lack of understanding of the fundamental neural circuitry that mediates relapse following withdrawal from chronic drug self-administration. Studies from our laboratory have demonstrated reinstatement of operant responding for drug-associated conditioned cues following chronic cocaine self-administration in rats. We showed that the basolateral amygdala (BLA) complex plays a key role in mediating the acquisition and expression of discrete conditioned cued effects, since inactivation of this nucleus greatly attenuates conditioned reinstatement, without affecting cocaine self-administration. Furthermore, reinstatement is dependent upon dopamine D1 receptors and also involves the central nucleus of the amygdala. In this competing renewal, studies are proposed to examine the neuropharmacological regulation of the BLA in conditioned reinstatement and to test the hypothesis that multiple neural pathways mediate different aspects of appetitive conditioning that occur during chronic drug self-administration. Specifically, we hypothesize that the BLA is a key regulator of discrete stimulus-reinforcer associations, but other brain regions, particularly areas of the prefrontal cortex and the nucleus accumbens, are critical for reinstatement evoked by discriminative conditioned stimuli that predict drug availability. In addition, we will extend the use of this relapse model across other classes of abused drugs by testing reinstatement of heroin-seeking behavior. These experiments provide an integrated approach aimed at understanding the neural basis of long-term conditioned associations produced by various drugs of abuse. Information gained from this project will provide direction for development of treatments for craving and for preventing relapse.